Palonosetron HCl, 1H-Benz[de]isoquinolin-1-one, 2-(3S)-1-azabicyclo[2.2.2]oct-3-yl-2,3,3aS,4,5,6-hexahydro-, monohydrochloride, of the following formula:
is a selective 5HT3-antagonist (prevention of chemotherapy-induced nausea and vomiting). It is marketed as a solution under the name Aloxi®. by Helsinn.
Palonosetron HCl and its cyclic amide precursor (referred to as Cp9532) are described in U.S. Pat. No. 5,202,333. Also disclosed is the preparation of Palonosetron HCl by reacting 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (referred to as Cp20774) with the diamine (referred to as Cp20771) providing the related amide (referred to as Cp9533), which is purified via it's hydrochloride salt (referred to as Cp9563). Then, Cp 9533 reacts with BuLi to provide the cyclic amide (referred to as Cp9532), which is then converted to Palonosetron by hydrogenation process. The process is illustrated by the following scheme:

The hydrogenation step is done in the presence of a mixture of acids, providing a mixture of Palonosetron salts, which are converted to the base, and then to Palonosetron HCl.
EP patent. No 430190 describes a process similar to the one disclosed in U.S. Pat. No. 5,202,333.
Another similar process is described in J. Med Chem. 1993, 36, however, in this journal, the hydrogenation is performed on the hydrochloride salt of Cp9532. This hydrogenation is performed in the presence of acids, such as acetic acid and perchloric acid, providing a mixture of Palonosetron salts, which is transformed to Palonosetron free base is and then converted to Palonosetron HCl, providing it in moderate yields.
The hydrogenation step for converting the cyclic amide (referred to as Cp9532) to Palonosetron HCl is described in Organic process Research & development, 1997, 1, 117; wherein the cyclic amide or its salt analogue is used for the reaction. The use of the salt and high amounts of catalyst are described herein, leading to a ratio of about 1:1 of the below depicted isomers. Also reported is the use of the free base form of the amide leading to a better ratio of isomers, but also to Palonosetron contaminated with the starting material, a cyclic amide, an impurity difficult to purify from.
According to the processes described in the above patents and journal articles, Palonosetron HCl is obtained as a mixture of R and S isomers at carbon No. 3. Typically, in the mixture of R and S isomers prepared according to these processes the R and S isomers are present in such mixture in a 1:2.1 to 1:3.3 ratio (see Table 3 of OPRD 1997, 1, 117-120) or 43:57 ratio (when obtained by hydrogenating as hydrochloride) and a 30:70 ratio (when hydrogenating as base) (see J Med Chem, 1993, 36, 2645-2657).
However, only the 3aS isomer is reported to possess a higher affinity for 5-HT (see Current Opinion in Investigational Drugs 2002 Vol. 3 No 10 page 1502-1507).
Hence, providing a process for producing Palonosetron salt in high yields, high purity, especially from the starting cyclic amide, and with a good isomeric ratio is of benefit.